Bone marrow transplantation (BMT) is a curative approach to treat hematological malignancies and other life-threatening disorders. The success of bone marrow transplantation (BMT) is limited by donor T lymphocyte-mediated lethal inflammation, called graft versus host disease (GVHD). As the donor T lymphocytes are important in bone marrow engraftment and in prevention of tumor recurrence, novel treatment strategies are needed to maintain donor T lymphocyte anti-tumor immunity (graft versus tumor; GVT) and suppress GVHD. Therapeutic stimulation of regulatory T cell (Treg) function is a novel approach to manage GVHD with preserved GVT. Our results show that augmentation of intestinal immune regulation may induce Tregs in vivo, with subsequent modulation of GVHD and preservation of GVT. We induce intestinal immune regulation or conditioning with a completely novel approach, with self-limited helminth colonization of the gut. Helminths stimulate T helper 2 (Th2) immune pathways. In this application, we propose that the Th2 pathways are critical in intestinal immune conditioning and lead to in vivo Treg generation. We will use murine nematode, Heligmosomoides bakeri (polygyrus) infection in MHC I/II major mismatch mouse model of severe acute GVHD. To assess the role of Th2 pathways in regulation of GVHD and in vivo induction of Tregs, we will employ complementary genetic and pharmacological approaches in mice. We will determine whether intestinal immune conditioning increases regulatory activity of Tregs. We will investigate the effect of helminth infection on GVT with A20 leukemia/lymphoma model. Our first long term goal is to dissect cellular as well as molecular immune regulatory pathways important in helminthic immune conditioning in preclinical models. Our second long term goal is to apply the knowledge from preclinical models to clinical bone marrow transplantation (BMT). No significant side effects associated with helminth infection have been reported in different immune suppressed patient groups so far. Targeting helminth-modulated signaling pathways using small molecules, helminth products or possibly even intact helminths may be a safe, potent and novel treatment for GVHD in BMT, while leaving the beneficial effect of GVT intact.